Astrocyte-derived exosomes regulate sperm miR-34c levels to mediate the transgenerational effects of paternal chronic social instability stress
The effects of chronically stressing male mice can be transmitted across generations by stress-specific changes in their sperm miRNA content, which induce stress-specific phenotypes in their offspring. However, how each stress paradigm alters the levels of distinct sets of sperm miRNAs is not known....
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Taylor & Francis Group
2025-12-01
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| Series: | Epigenetics |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/15592294.2025.2457176 |
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| author | Alexandre Champroux Mitra Sadat-Shirazi Xuan Chen Jonathan Hacker Yongjie Yang Larry A. Feig |
| author_facet | Alexandre Champroux Mitra Sadat-Shirazi Xuan Chen Jonathan Hacker Yongjie Yang Larry A. Feig |
| author_sort | Alexandre Champroux |
| collection | DOAJ |
| description | The effects of chronically stressing male mice can be transmitted across generations by stress-specific changes in their sperm miRNA content, which induce stress-specific phenotypes in their offspring. However, how each stress paradigm alters the levels of distinct sets of sperm miRNAs is not known. We showed previously that exposure of male mice to chronic social instability (CSI) stress results in elevated anxiety and reduced sociability specifically in their female offspring across multiple generations because it reduces miR-34c levels in sperm of stressed males and their unstressed male offspring. Here, we describe evidence that astrocyte-derived exosomes (A-Exos) carrying miR-34c mediate how CSI stress has this transgenerational effect on sperm. We found that CSI stress decreases miR-34c carried by A-Exos in the prefrontal cortex and amygdala, as well as in the blood of males. Importantly, miR-34c A-Exos levels are also reduced in these tissues in their F1 male offspring, who despite not being exposed to stress, exhibit reduced sperm miR-34c levels and transmit the same stress-associated traits to their male and female offspring. Furthermore, restoring A-Exos miR-34c content in the blood of CSI-stressed males by intravenous injection of miR-34c-containing A-Exos restores miR-34c levels in their sperm. These findings reveal an unexpected role for A-Exos in maintaining sperm miR-34c levels by a process that when suppressed by CSI stress mediates this example of transgenerational epigenetic inheritance. |
| format | Article |
| id | doaj-art-3b9d08dc486b435bbd58f811f0b42f31 |
| institution | Kabale University |
| issn | 1559-2294 1559-2308 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Epigenetics |
| spelling | doaj-art-3b9d08dc486b435bbd58f811f0b42f312025-01-27T10:48:11ZengTaylor & Francis GroupEpigenetics1559-22941559-23082025-12-0120110.1080/15592294.2025.2457176Astrocyte-derived exosomes regulate sperm miR-34c levels to mediate the transgenerational effects of paternal chronic social instability stressAlexandre Champroux0Mitra Sadat-Shirazi1Xuan Chen2Jonathan Hacker3Yongjie Yang4Larry A. Feig5Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USADepartment of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USADepartment of Neuroscience, Tufts University School of Medicine, Boston, MA, USADepartment of Neuroscience, Tufts University School of Medicine, Boston, MA, USADepartment of Neuroscience, Tufts University School of Medicine, Boston, MA, USADepartment of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USAThe effects of chronically stressing male mice can be transmitted across generations by stress-specific changes in their sperm miRNA content, which induce stress-specific phenotypes in their offspring. However, how each stress paradigm alters the levels of distinct sets of sperm miRNAs is not known. We showed previously that exposure of male mice to chronic social instability (CSI) stress results in elevated anxiety and reduced sociability specifically in their female offspring across multiple generations because it reduces miR-34c levels in sperm of stressed males and their unstressed male offspring. Here, we describe evidence that astrocyte-derived exosomes (A-Exos) carrying miR-34c mediate how CSI stress has this transgenerational effect on sperm. We found that CSI stress decreases miR-34c carried by A-Exos in the prefrontal cortex and amygdala, as well as in the blood of males. Importantly, miR-34c A-Exos levels are also reduced in these tissues in their F1 male offspring, who despite not being exposed to stress, exhibit reduced sperm miR-34c levels and transmit the same stress-associated traits to their male and female offspring. Furthermore, restoring A-Exos miR-34c content in the blood of CSI-stressed males by intravenous injection of miR-34c-containing A-Exos restores miR-34c levels in their sperm. These findings reveal an unexpected role for A-Exos in maintaining sperm miR-34c levels by a process that when suppressed by CSI stress mediates this example of transgenerational epigenetic inheritance.https://www.tandfonline.com/doi/10.1080/15592294.2025.2457176Epigenetic inheritancestressexosomesastrocytesspermmiRNAs |
| spellingShingle | Alexandre Champroux Mitra Sadat-Shirazi Xuan Chen Jonathan Hacker Yongjie Yang Larry A. Feig Astrocyte-derived exosomes regulate sperm miR-34c levels to mediate the transgenerational effects of paternal chronic social instability stress Epigenetics Epigenetic inheritance stress exosomes astrocytes sperm miRNAs |
| title | Astrocyte-derived exosomes regulate sperm miR-34c levels to mediate the transgenerational effects of paternal chronic social instability stress |
| title_full | Astrocyte-derived exosomes regulate sperm miR-34c levels to mediate the transgenerational effects of paternal chronic social instability stress |
| title_fullStr | Astrocyte-derived exosomes regulate sperm miR-34c levels to mediate the transgenerational effects of paternal chronic social instability stress |
| title_full_unstemmed | Astrocyte-derived exosomes regulate sperm miR-34c levels to mediate the transgenerational effects of paternal chronic social instability stress |
| title_short | Astrocyte-derived exosomes regulate sperm miR-34c levels to mediate the transgenerational effects of paternal chronic social instability stress |
| title_sort | astrocyte derived exosomes regulate sperm mir 34c levels to mediate the transgenerational effects of paternal chronic social instability stress |
| topic | Epigenetic inheritance stress exosomes astrocytes sperm miRNAs |
| url | https://www.tandfonline.com/doi/10.1080/15592294.2025.2457176 |
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